Benzodiazepine modulation of GABA(A) receptor opening frequency depends on activation context: a patch clamp and simulation study.

Abstract:

:Benzodiazepines (BDZs) are GABA(A) receptor modulators with anxiolytic, hypnotic, and anticonvulsant properties. BDZs are understood to potentiate GABA(A) receptor function by increasing channel opening frequency, in contrast to barbiturates, which increase channel open duration. However, the in vitro evidence demonstrating increased opening frequency involved prolonged exposure to sub-saturating GABA concentrations, conditions most similar to those found in extrasynaptic areas. In contrast, synaptic GABA(A) receptors are transiently activated by high GABA concentrations. To determine if BDZ modulation of single-channel opening frequency would be different for BDZ-sensitive receptors activated under synaptic versus extrasynaptic conditions, a combination of patch clamp recording and kinetic modeling was used. Consistent with the original experimental findings, BDZs were found to increase receptor affinity for GABA by decreasing the unbinding rate. While this mechanism was predicted to increase opening frequency under extrasynaptic conditions, simulations predicted that the same mechanism under synaptic conditions would increase the number, but not the frequency, of single-channel openings. Thus, a single mechanism (slower GABA unbinding) can produce differential changes in opening frequency under synaptic versus extrasynaptic conditions. The functional impact of BDZs on GABA(A) receptors therefore depends upon the physiological context of receptor activation.

journal_name

Epilepsy Res

journal_title

Epilepsy research

authors

Bianchi MT,Botzolakis EJ,Lagrange AH,Macdonald RL

doi

10.1016/j.eplepsyres.2009.03.007

subject

Has Abstract

pub_date

2009-08-01 00:00:00

pages

212-20

issue

2-3

eissn

0920-1211

issn

1872-6844

pii

S0920-1211(09)00076-X

journal_volume

85

pub_type

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